Lung transplant recipients, 97% of whom are adults, are the fastest growing segment of solid organ transplant patients. This growth is expected to continue due to increasing incidence of advanced lung disease as well as increasing lung donor utilization rates. Unfortunately, there have not been parallel improvements in patient outcomes. Median long-term patient survival after lung transplant is only 5.5 years, a figure that lags all other commonly transplanted organs. These poor outcomes reflect the high burden of both non-infectious and infectious complications. Foremost among these is cytomegalovirus (CMV), the most common opportunistic infection after lung transplantation. It affects > 40% of all serologically at-risk lung transplant recipients despite current prophylaxis. Prevention of CMV infection is of paramount importance since its development is associated with higher rates of long-term graft failure and death. This graft failure, known as chronic lung allograft dysfunction (CLAD), is the primary reason for poor long-term survival and occurs in >50% of lung transplant recipients within five years. Despite its importance, our understanding of the clinical risks and immunological mechanisms that lead to CLAD is rudimentary and based upon small, single center studies. Thus, there is a critical unmet need for scientifically rigorous, well-designed multicenter lung transplant research studies that directly address these major graft-limiting complications. To meet this need, we propose creation of the Lung Transplant Clinical Trials Network (LT-CTN) through CTOT to conduct key clinical and mechanistic studies of CMV and CLAD in lung transplant. Our team represents key clinical and research groups of five of the leading academic lung transplant centers in North America (Duke, Cleveland Clinic, Johns Hopkins, University of California - Los Angeles, and University of Toronto). By addressing the major causes of morbidity and graft failure after lung transplantation, our proposed studies have the potential to directly impact clinical practice for CMV prevention and advance mechanistic understanding of CLAD. Furthermore, because CMV infection and chronic allograft dysfunction are complications relevant to transplantation of other solid organs, our mechanistic studies are likely to reveal host responses important in other solid organ transplant populations. Thus, we have the leadership, clinical research expertise and basic research depth to successfully accomplish the proposed studies, contribute to the overall impact of the CTOT program, and help improve patient outcomes.